Soon after the initial discovery of human immunodeficiency virus (HIV) as the cause of acquired immune deficiency syndrome (AIDS), a very small group of HIV-infected patients has been identified to remain AIDS-free for several decades. These so-called HIV elite controllers (EC) usually have relatively high CD4+ T cell counts and are able to maintain clinically undetectable plasma HIV-1 RNA level (HIV RNA <50 copies/mL) during a prolonged period of time in the absence of any antiretroviral treatment (ART). During recent years, extensive research has been made to define mechanisms by which these rare individuals control HIV.
Interestingly, the EC status suggests a low activation profile of T cells and the existence of a unique MHC-1b/E-restricted CD8+ T cells population able to suppress the early activation of pathogenic HIV antigen-presenting CD4+ T cells (Lu et al. (2016) Front. Immunol. 7:134). Furthermore, recent advances in the field of SIV vaccinology also have highlighted the role of MHC-1b/E-restricted CD8+ T cell responses in controlling SIV infection in rhesus macaques (Hansen et al. (2013) Science 24; 340(6135):1237874; Hansen et al. (2016) Science; 351(6274), 714-20; Lu et al. (2012) Cell Rep. 2(6), 1736-46; Andrieu et al. (2014) Front Immunol. 5:297). These observations have suggested alternative strategies for developing an HIV vaccine.
Indeed, since an activated state of the CD4+ T cell is a prerequisite for productive HIV infection also in vivo, and thus replication in quiescent CD4+ T cells is essentially nonproductive and generally abortive, it has been hypothesized that it might be possible to suppress viral replication by interfering with the CD4+ T cell activation. Therefore, several groups have tempted to suppress virus-specific CD4+ T cell activation with vaccines that induce MHC-1b/E-restricted CD8+ cells.
For example, Andieu et al. have developed a vaccine able to induce MHC-1b/E-restricted CD8+ T cells in macaques. This vaccine consisted of inactivated simian immunodeficiency virus (SIV) particles associated with a tolerogenic adjuvant, such as, for example, Lactobacillus plantarum. Although this vaccine strategy effectively immunized and induced suppressive MHC-1b/E-restricted CD8+ T cells in Chinese macaques, macaques of Indian origin that were immunized with the same adjuvanted vaccine were not protected.
Hansen et al., by modifying cytomegalovirus (CMV) vectors determinants that control unconventional T cell priming, have shown that it was possible to uniquely tailor the CD8+ T cell response in order to maximize prophylactic or therapeutic protection. Specifically, it was found that the use of such rhesus cytomegalovirus vectors expressing SIV protein in rhesus macaques (RMs) induces post-challenge sterile protection against SIV. However, this protection was effective in only 50% of vaccinated RMs.
Globally, these results have expanded the current paradigm from one focused on a preventive HIV vaccine to one in which an immunotherapy for HIV/AIDS can be an essential part of the fight against this pandemic. Thus, in addition to a preventive vaccine, there remains a need for an effective therapy to treat individuals living with HIV-1.
Based on the discovery of new biological properties of type III interferon (IFN-III), the inventors propose to improve existing vaccine (i.e., induction of a suppressive MHC-1b/E-restricted CD8+ T cell population) strategies for preventing or treating HIV and others infectious diseases.
In particular, the Applicant demonstrates that type III interferon may greatly potentiate existing CD8 suppressive vaccines. Indeed, on the contrary of type I interferons, type III interferons appear to have a more specialized role in innate antiviral defense and do not inhibit the initiation of the adaptative immune reaction after HIV infection. In particular, IFN-III can prevent or limit virus replication without inhibiting the proliferation of CD4+ T cells that respond to HIV infection.
The Applicant further demonstrates that the blockade of interferon alpha (IFN-α) as a supplement to a CD8 suppressive vaccine might potentiate type III interferon and thus greatly improve the vaccine efficacy. Indeed, IFN-α is a paradoxical type I interferon cytokine that can prevent or limit virus replication while promoting a deleterious chronic immune activation. Because chronic immune activation is necessary for HIV replication, IFN-α thus can play a deleterious role during HIV infection. Moreover, as demonstrated by the inventors, IFN-α has an anti-proliferative activity that inhibits the proliferation of CD4+ T cells, and therefore leads to immune decline, virus replication and AIDS in infected patients. Thus, by the blockade of IFN-α, the Applicant aims to potentiate type III interferon activities, therefore promoting a lower chronic immune activation and a better response of CD4+ T cells.
In the present invention, the Applicant thus provides a novel method for preventing or treating an infectious disease in a subject in need thereof comprising administering to the subject:                1) a CD8 vaccine specific for at least one infectious disease-related antigen,        2) an agent neutralizing circulating alpha interferon and/or an agent blocking interferon alpha signaling, and/or        3) a type III interferon and/or an agent stimulating the production of type III interferon.        